Dendritic Langerhans Cells Research Articles

The cellular microenvironment and neoplastic population in mycosis fungoides skin lesions: a clinicopathological correlation.

The cellular microenvironment has been proven to play a crucial role in solid tumours and seems to be important in haematologic malignancies, however, it has not been adequately investigated in primary cutaneous Tcell lymphomas. The aim of this study was to register the composition of the cellular microenvironment in mycosis fungoides skin lesions and correlate the composing parameters with the clinical data and follow-up results. The presence of eosinophilic polymorphonuclear leukocytes, Blymphocytes, CD68+ macrophages, and CD1a+ epidermal Langerhans and antigen-presenting dermal dendritic cells, as well as their relation to clinicopathological parameters, were studied in 16 mycosis fungoides cases of different disease stages. The presence and nature of the participating Tcell populations was also investigated. CD8+ tumour infiltrating Tcells and CD56+ cells were found among neoplastic CD4+ Tcells in the lesions. Generally, eosinophils and Blymphocytes were absent or in low numbers, regardless of clinical presentation, contrary to tumourous lesions. Macrophages and CD1a+ cells were constantly present, even in early-stage mycosis fungoides. The reduced presence of the CD1a+ population was associated with resistance to therapy (x2; p=0.012). There is a striking difference in cellular microenvironment composition between early and advanced mycosis fungoides lesions.

The hepatocyte growth factor (HGF)–MET receptor tyrosine kinase signaling pathway: Diverse roles in modulating immune cell functions

Hepatocyte growth factor (HGF) signaling via the MET receptor is essential for embryonic development and tissue repair. On the other hand, deregulated MET signaling promotes tumor progression in diverse types of cancers. Even though oncogenic MET signaling remains the major research focus, the HGF–MET axis has also been implicated in diverse aspects of immune cell development and functions. In the presence of other hematopoietic growth factors, HGF promotes the development of erythroid, myeloid and lymphoid lineage cells and thrombocytes. In monocytes and macrophages responding to inflammatory stimuli, induction of autocrine HGF–MET signaling can contribute to tissue repair via stimulating anti-inflammatory cytokine production. HGF–MET signaling can also modulate adaptive immune response by facilitating the migration of Langerhans cells and dendritic cells to draining lymph nodes. However, MET signaling has also been shown to induce tolerogenic dendritic cells in mouse models of graft-versus-host disease and experimental autoimmune encephalomyelitis. HGF–MET axis is also implicated in promoting thymopoiesis and the survival and migration of B lymphocytes. Recent studies have shown that MET signaling induces cardiotropism in activated T lymphocytes. Further understanding of the HGF–MET axis in the immune system would allow its therapeutic manipulation to improve immune cell reconstitution, restore immune homeostasis and to treat immuno-inflammatory diseases.

Application of Microneedles to Skin Induces Activation of Epidermal Langerhans Cells and Dermal Dendritic Cells in Mice.

An adequate immune response to percutaneous vaccine application is generated by delivery of sufficient amounts of antigen to skin and by administration of toxin adjuvants or invasive skin abrasion that leads to an adjuvant effect. Microneedles penetrate the stratum corneum, the outermost layer of the skin, and enable direct delivery of vaccines from the surface into the skin, where immunocompetent dendritic cells are densely distributed. However, whether the application of microneedles to the skin activates antigen-presenting cells (APCs) has not been demonstrated. Here we aimed to demonstrate that microneedles may act as a potent physical adjuvant for successful transcutaneous immunization (TCI). We prepared samples of isolated epidermal and dermal cells and analyzed the expression of major histocompatibility complex (MHC) class II and costimulatory molecules on Langerhans or dermal dendritic cells in the prepared samples using flow cytometry. The expression of MHC class II and costimulatory molecules demonstrated an upward trend in APCs in the skin after the application of 500- and 300-µm microneedles. In addition, in the epidermal cells, application of microneedles induced more effective activation of Langerhans cells than did an invasive tape-stripping (positive control). In conclusion, the use of microneedles is likely to have a positive effect not only as an antigen delivery system but also as a physical technique inducing an adjuvant-like effect for TCI.

Biocompatible Mater Constructed Microneedle Arrays as a Novel Vaccine Adjuvant- Delivery System for Cutaneous and Mucosal Vaccination.

Vaccination is the most cost-effective and the best prophylactic strategy for the treatment of many diseases and, therefore, is widely used to improve human health. However, currently, most vaccines are given by injection which has a number of intrinsic disadvantages, such as inoculation needing professionals, waste metal needle pollution and infection, and low vaccination compliance. To overcome these drawbacks, in the past two decades a variety of microneedles have been developed and these are increasingly being widely tried to deliver vaccines due to many prominent advantages, such as their convenience, and effectiveness, over other delivery systems. In particular, the biocompatible material-constituted microneedle arrays (bioMMAs) that are fabricated with biocompatible materials in the form of a matrix or formulated micro/nanoparticles, such as liposomes, PLA/PLGA/ chitosan nanoparticles, hydrogels, polyelectrolyte multiplelayers (PEMs), plasmids, and nonvirulent pathogens, have proven an effective and stable vaccine adjuvant-delivery system (VADS) allowing painless vaccination via the cutaneous or mucosal route by minimally trained workers or by self-administration. When given to mammals through the skin or oral mucosa where affluent professional antigen-presenting cells (APCs), such as Langerhans cells, dendritic cells and macrophages, are actively patrolling for immune surveillance, the bioMMAs can efficiently elicit robust systemic as well as mucosal immunoresponses against the loaded antigens. In addition, when different vaccine adjuvants, such as TLR (toll-like receptor) ligands, have been incorporated, the bioMMAs can govern and redirect the immunoresponse toward a Th1, Th2 or a mixed Th1/Th2 pathway to establish cellular and humoral immunity to the target pathogens. In this review, various types of bioMMAs used as a VADS are described to show the latest advances and their diverse uses and potential applications in vaccine-related fields.

A gain-of-function CCR4 mutations in adult T-cell leukemia/lymphoma (ATL) enhance the chemotactic abilities and P13K/AKT activation

High expression of the CC chemokine receptor 4 (CCR4) has been identified as a hallmark gene in ATL-an aggressive peripheral T-cell neoplasm. CCR4 is a chemokine receptor, which has a critical role in immune cell trafficking including Th2, T-regs and skin homing memory T-cells. CCR4 ligands, CCL17 and CCL22 are produced in lymph nodes and skin from dendritic cells, macrophages and Langerhans cells. Most ATL cases express surface CCR4 (90%) and infiltrate lymph nodes and skin. We performed RNA-Seq on two primary ATL cases and discovered recurrent nonsense mutations in CCR4. Through an extended analysis using Sanger sequencing, CCR4 mutations were detected in 14/53 ATL samples (26%) and consisted exclusively of nonsense or frameshift mutations that truncated the coding region at C329, Q330 or Y331 in the carboxyl-terminus. We hypothesized that the mutant CCR4 isoforms might enhance chemotaxis of the affected cells to CCR4 ligands. A chemotaxis assay using 32D beta, a mouse myeloid cell line and ED40515 (+), an ATL cell line, clarified that the ectopic expression of CCR4-Q330* but not CCR4-WT transduced cells enhanced the chemotactic ability of the transduced cells toward CCL17 and CCL22. To define the mechanism of the enhanced chemotactic ability, we examined the change in surface CCR4 levels after CCL22 exposure in CCR4-WT-and CCR4-Q330*-reconstituted ED40515 (+) cells. Compared with CCR4-WT, CCR4 internalization in CCR4-Q330*-reconstituted cells was significantly impaired. Thus, the ATL CCR4 mutants manifested impaired desensitization by ligand, which likely contributed to the enhanced chemotaxis of cells bearing these mutants. We explored the influence of the ATL CCR4 mutants on PI(3) kinase (PI3K)-dependent activation of AKT since it has been reported that binding of CCL22 to CCR4 activates AKT in CEM leukemic T-cells and in human Th2 cells. CCR4-Q330* reconstituted ED40414 (+) cells showed strong activation of AKT with CCL22 ligation compared with CCR4-WT reconstituted cells. The AKT activation was inhibited by the pan-P13K inhibitor, BKM120, indicating that the CCR4-mediated AKT activation was PI3K dependent. Lastly, we tested whether the acquisition of CCR4 mutations by ATL cells imparts a selective growth advantage relative to cells with wild-type CCR4. CCR4-Q330*-reconstituted cells had a selective growth advantage in the presence of CCL22, supporting, at least in part, the hypothesis that CCR4 mutations provided the affected cells with a positive selection pressure through CCL22 ligation that contributed to the ATL pathogenesis. Our findings provide a rationale for a clinical trial to test whether inhibition of CCR4 signaling might have a therapeutic potential for patients with ATL.

Pulmonary Langerhans cell histiocytosis

Pulmonary Langerhans cell histiocytosis is regarded as a reactive proliferation of the dendritic Langerhans cell population stimulated by chronic tobacco-derived plant proteins due to incomplete combustion but can also occur in childhood as a tumor-like systemic disease. Currently, both these forms cannot be morphologically distinguished. In the lungs a nodular proliferation of Langerhans cells occurs in the bronchial mucosa and also peripherally in the alveolar septa with an accompanying infiltration by eosinophilic granulocytes and destruction of the bronchial wall. Langerhans cells can be selectively detected with antibodies against CD1a and langerin. In the reactive isolated pulmonary form, abstinence from tobacco smoking in most patients leads to regression of infiltration and improvement of symptoms. In high-resolution computed tomography (HRCT) the small star-like scars can still be detected even after complete cessation of tobacco smoking.

Dendritic Cells Cause Bone Lesions in a New Mouse Model of Histiocytosis.

Langerhans cell histiocytosis (LCH) is a rare disease caused by the clonal accumulation of dendritic Langerhans cells, which is often accompanied by osteolytic lesions. It has been reported that osteoclast-like cells play a major role in the pathogenic bone destruction seen in patients with LCH and these cells are postulated to originate from the fusion of DCs. However, due to the lack of reliable animal models the pathogenesis of LCH is still poorly understood. In this study, we have established a mouse model of histiocytosis- recapitulating human disease for osteolytic lesions seen in LCH patients. At 12 weeks after birth, severe bone lesions were observed in our multisystem histiocytosis (Mushi) model, when CD8α conventional dendritic cells (DCs) are transformed (MuTuDC) and accumulate. Most importantly, our study demonstrates that bone loss in LCH can be accounted for the transdifferentiation of MuTuDCs into functional osteoclasts both in vivo and in vitro. Moreover, we have shown that injected MuTuDCs reverse the osteopetrotic phenotype of oc/oc mice in vivo. In conclusion, our results support a crucial role of DCs in bone lesions in histiocytosis patients. Furthermore, our new model of LCH based on adoptive transfer of MuTuDC lines, leading to bone lesions within 1–2 weeks, will be an important tool for investigating the pathophysiology of this disease and ultimately for evaluating the potential of anti-resorptive drugs for the treatment of bone lesions.

Abstract 3936: Frequent gain-of-function CCR4 mutations in adult T-cell leukemia/lymphoma (ATLL)

Abstract High expression of CC chemokine receptor 4 (CCR4) has been identified as a hallmark gene in ATLL, an aggressive peripheral T-cell neoplasm. CCR4 is a chemokine receptor, which has a critical role in immune cell trafficking. CCR4 ligands, CCL17 and CCL22, were produced in lymph nodes and skin from dendritic cells, macrophages and Langerhans cells. Most ATLL cases express surface CCR4 (90%) and infiltrate to lymph nodes and skin. These observations suggest that CCR4 could have a role in ATLL biology, but it is still unclear whether dysregulation of CCR4 function contributes to ATLL pathogenesis. We performed RNA-Seq for two primary ATLL cases and discovered recurrent non-sense mutations in CCR4. Though an extended analysis using Sanger sequencing, CCR4 mutations were detected in 14/53 ATLL samples (26%) and consisted exclusively of nonsense or frameshift mutations that truncated the coding region at C329, Q330 or Y331 in the carboxy-terminus. In 5 cases for which paired normal DNA was available, three different CCR4 mutations were detected only in the ATLL cells (Q330*; Q330 frameshift; Y331*), demonstrating that they were acquired somatically during malignant transformation or progression. Chemotaxic assay using 32Dβ, a mouse myeloid cell line, and ED40515(+), an ATLL cell line, clarified that the ectopic expression of CCR4-Q330* enhanced the chemotactic ability of the transduced cells toward CCL17 and CCL22 rather than CCR4-WT transduced cells. To understand the mechanism of this enhanced chemotactic ability, we studied the change in surface CCR4 levels after CCL22 exposure in CCR4-WT-and CCR4-Q330*-reconstituted ED40515(+) cells. Compared with CCR4-WT, CCR4 internalization in CCR4-Q330*-reconstituted cells was significantly impaired. Thus, the ATLL CCR4 mutants impair desensitization by ligand, which likely contributes to the enhanced chemotaxis of cells bearing these mutants. We explored the influence of the ATLL CCR4 mutants on PI3K/AKT signaling by immunoblot analysis and phosphor-flow analysis. CCR4-Q330*-reconstituted ED40515(+) showed strong activation of AKT with CCL22 ligation compared with CCR4-WT-reconstituted cell. Furthermore, we tested whether the acquisition of CCR4 mutations by ATLL cells imparts a selective growth advantage relative to cells with wild type CCR4. CCR4-Q330*-reconstituted cells had a selective growth advantage in the presence of CCL22, supporting at least in part the hypothesis that CCR4 mutation are able to provide the affected cells a positive selection pressure through CCL22 ligation and contributes to ATLL pathogenesis. Our findings implicate somatic gain-of-function CCR4 mutations in the pathogenesis of ATLL and suggest that inhibition of CCR4 signaling might have therapeutic potential in this refractory malignancy. Citation Format: Masao Nakagawa, Roland Schmitz, Wenming Xiao, Carolyn K. Goldman, Weihong Xu, Yandan Yang, Xin Yu, Thomas A. Waldmann, Louis M. Staudt. Frequent gain-of-function CCR4 mutations in adult T-cell leukemia/lymphoma (ATLL). [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 3936. doi:10.1158/1538-7445.AM2015-3936

Immune defence in the lymphatic system of the skin

ZusammenfassungAls Grenzorgan zwischen Außen und Innen ist die Haut prädestiniert für häufigen und intensiven Kontakt mit Pathogenen und ist daher immunologisch besonders gerüstet. Das Immunsystem schützt die Integrität des Organismus mit angeborenen Komponenten wie der physikalisch-chemischen Barrierefunktion der Haut, den Phagozytosezellen und dem Komplementsystem. Das Netzwerk der Langerhans-Dendriten in der Epidermis ermöglicht sofortiges Aufspüren und zügigen Transport von Antigenmaterial in den regionären Lymphknoten und Auslösung einer spezifischen Immunantwort durch T- und B-Zellen. Für immunologische Vorgänge ist die Passage durch die Lymphbahnen entscheidend, da Zellen und Lymphbahnen vielfältig wechselwirken. Einerseits werden durch die Interaktion von dendritischen Rezeptoren mit antigenen Strukturen intrazelluläre Signale getriggert, die die Wanderung durch die Lymphbahn zum Lymphknoten über Chemokine und Chemokinrezeptoren ermöglichen. Die Langerhans-Dendriten andererseits verändern sich auch selbst phänotypisch während der Wanderung durch die Lymphbahnen: sie verlieren die Phagozytosefähigkeit zugunsten der verstärkten Synthese von MHC-Molekülen und werden zu antigen-präsentierenden Zellen.

230 CHARACTERISTICS OF BLASTS IN THE PERIPHERAL BLOOD AND BONE MARROW OF THE PATIENTS WITH MDS TREATED WITH 5-AZACITADINE USING MULTIPARAMETRIC FLOW CYTOMETRY

To date no hematopoietic progenitors of dendritic Langerhans' cells (DLC), which represent an highly efficient class of antigen presenting cells, have been identified or the cytokines they elaborate have been defined. Here we describe an acute leukemia patient whose blasts (90–96% in peripheral blood and bone marrow) had a phenotype consistent with putative progenitors of DLC. The patient was treated with ara-C and VP-16 but did not achieve remission. The blasts had lobulated nuclei, no cytoplasmic vacuolation or Auer rods and were weakly positive for acid phosphatase and non-specific esterase and negative for PAS, granzyme A, dipeptidyl aminopeptidase IV, ATPase/ADPase and lysozyme production. The blasts were positive for CD1a, CD4, CD16, CD35, HLADR, HLADQ, CD11b, CD11c, CD14, CD33, CD34, CD11a, CD71, CD19, CD25, IL-2Rβ and negative for CD2, CD7, CD8, CD10, CD22, CD56, CD57, surface or cytoplasmic CD3, TCRδ and TCRβ, HTLV-1p19 and P-glycoprotein. On liquid culture with or without 5 × 10−9M 12-O-tetradecanoylphorbol-13-acetate (TPA) for 3 days, the blasts formed aggregates of proliferating and elongating cells on the wall of the flasks with a decline in CD34, numerous dendritic processes appeared on the cells and there was strong positivity for ATPase/ADPase, but no other changes in phenotype. No macrophages were observed, indicating derivation from separate DLCs. Cytogenetic analysis showed chromosomal abnormalities and electron microscopy showed Birbeck granules. Southern blotting of DNA showed rearangement of one allele for both JH and TCRβ but not HTLV-1 related sequences. Culture supernatants from blasts cultured with or without TPA showed the production of large amounts of IL-8, IL-6, TNF-α, MIP-1α, IL-10 and interferon γ and modest amounts of IL-1α, GM-CSF and stem cell factor. The presence not only of CD1a, HLADR, HLADQ and many other characteristics including Birbeck granules, but also differentiation along the lines of DLC with appearance of dendritic processes on the cells and expression of ATPase/ADPase activity, indicate that the leukemic blasts in our patient represented at leukemic counterpart of normal progenitors of DLC and the leukemia a new entity which could possibly be classified as AML-M8. Lastly, many pro-inflammatory cytokines produced by DLC could contribute to inflammation and IL-10 to immunosuppression.

Oral administration of paeoniflorin attenuates allergic contact dermatitis by inhibiting dendritic cell migration and Th1 and Th17 differentiation in a mouse model.

Allergic contact dermatitis (ACD) is a hapten-specific CD4(+) T-cells mediated inflammatory response of the skin. Its pathomechanism involves 2 phases, an induction phase and an elicitation phase. Langerhans cells (LCs) and dendritic cells (DCs) in the skin play key roles in presenting low molecular weight chemicals (haptens) to the lymph nodes. Therefore, inhibition of the migration of LCs or DCs and T-cell proliferation is each expected to control ACD disease. To explore the effectiveness of paeoniflorin (PF) on the migration of LCs and T-cell proliferation in vivo, we establish a murine model of ACD, promoted by repeated exposure to an allergen (specifically 1-Chloro-2,4-dinitrobenzene (DNCB)). Administration of PF inhibits DC migration in this DNCB-induced model in the induction phase. As a result, epidermal LC density in the elicitation phase increased in PF-treated mice when compared to PF-untreated mice. At the same time, PF reduced IFN-γ(+)CD4(+) and IL-17(+)CD4(+) T cells proliferation (but not IL-4(+)CD4(+) T cells proliferation), leading to an attenuated cutaneous inflammatory response. Consistent with this T-cell proliferation profile, secretions of IFN-γ and IL-17 were reduced and IL-10 secretion increased in PF-treated mice, but production of IL-4 and IL-5 remained unchanged in the skin and blood samples. These results suggest that oral administration of PF can treat and prevent ACD effectively through inhibition of DC migration, and thus decrease the capacity of DCs to stimulate Th1 and Th17 cell differentiation and cytokine production.

Myeloid human cell lines lack functional regulation of aryl hydrocarbon receptor-dependent phase I genes.

Primary dendritic cells and myeloid cell lines are used to assess the skin sensitization hazard in in vitro approaches. The aryl hydrocarbon receptor (AhR) modulates expression of CYP enzymes which play a significant role in the bioactivation of various xenobiotics. These studies revealed a strong constitutive expression of the AhR in primary human monocytes, monocyte-derived immature dendritic cells (iDC) and cord blood-derived Langerhans cells (LC). In contrast, mRNA and protein expression of AhR was hardly detectable in the cell lines THP-1 and MUTZ-3. U937 cells and MUTZ-3-derived dendritic (MUTZ-DC) or Langerhans cells (MUTZ-LC) showed about half the expression of AhR compared to iDC. Incubation of cells with the specific AhR-inducer benzo[a]anthracene resulted in an upregulation of CYP and IL-1β mRNA expression in primary monocytes and iDC. CYP1A1 but not CYP1B1 and IL-1β expression was increased by benzo[a]anthracene in these cell lines except for U937 cells. AhR-independent CYP genes were not regulated by benzo[a]anthracene. Constitutive mRNA expression of other non AhR-dependent CYP enzymes was higher in some of the cell lines compared to the corresponding primary cells. This study demonstrates significant differences in expression and regulation of phase I genes in cell lines currently used for in vitro skin sensitization hazard assessment compared to primary cells. Additional studies are required regarding the combination of cutaneous xenobiotic metabolizing enzymes and APC-sensitization for the development of valid in vitro models for skin sensitization assessment.

Chloroquine promotes IL-17 production by CD4+ T cells via p38-dependent IL-23 release by monocyte-derived Langerhans-like cells.

Recent studies suggest a role for autophagy in the secretion of IL-1 cytokines regulating the development of inflammatory diseases. The antimalarial drug and autophagy/lysosome inhibitor chloroquine (CHQ) is considered as potential trigger of drug-induced or drug-aggravated psoriasis, in which Th17 cells sustain a persistent inflammation. In this study, we investigated the effect of CHQ on human monocyte-derived Langerhans-like cells (MoLC) and dendritic cells (MoDC) in response to IL-1β. The presence of CHQ reduced IL-12p70 release in both subsets, but surprisingly increased IL-6 production in MoDC and IL-23 in MoLC. Importantly, CHQ-treated MoLC promoted IL-17A secretion by CD4(+) T cells and elevated RORC mRNA levels, whereas IFN-γ release was reduced. The dysregulation of IL-12 family cytokines in MoLC and MoDC occurred at the transcriptional level. Similar effects were obtained with other late autophagy inhibitors, whereas PI3K inhibitor 3-methyladenine failed to increase IL-23 secretion. The modulated cytokine release was dependent on IL-1 cytokine activation and abrogated by a specific IL-1R antagonist. CHQ elevated expression of TNFR-associated factor 6, a common intermediate in IL-1R and TLR-dependent signaling. Accordingly, treatment with Pam3CSK4 and CHQ enhanced IL-23 release in MoLC and MoDC. CHQ inhibited autophagic flux, confirmed by increased LC3-II and p62 expression, and activated ERK, p38, and JNK MAPK, but only inhibition of p38 abrogated IL-23 release by MoLC. Thus, our findings indicate that CHQ modulates cytokine release in a p38-dependent manner, suggesting an essential role of Langerhans cells and dendritic cells in CHQ-provoked psoriasis, possibly by promoting Th17 immunity.

A Challenging Cause of Chronic Diarrhea

A Challenging Cause of Chronic Diarrhea

Efficient transfer of HIV-1 in trans and in cis from Langerhans dendritic cells and macrophages to autologous T lymphocytes

The chronology of HIV infection in mucosal tissue after sexual transmission is unknown. Several potential HIV target cells are present at these sites, including dendritic cells, macrophages, and CD4(+) T lymphocytes. Dendritic cells and macrophages are antigen-presenting cells (APCs) and are thus involved in cross-talk with T cells. This close contact may favor efficient HIV-1 transfer to T lymphocytes, resulting in rapid HIV-1 dissemination. We investigated the role of APCs in HIV transfer to T cells by incubating Langerhans cells and interstitial dendritic cells (IDCs) or monocyte-derived macrophages (MDMs) with HIV for 2 h before addition of uninfected autologous CD4(+) T lymphocytes. HIV infection was recorded after different time points. Following staining, the measurement of intracellular p24 in the different cell populations was analyzed by flow cytometry. We showed that Langerhans cells/IDCs and macrophages efficiently transferred HIV to CD4(+) T cells. Interestingly, a rapid HIV transfer in trans predominated in MDMs, whereas cis transfer mainly occurred in Langerhans cells/IDC cocultures. Neutralizing antibody 2G12, added to HIV-loaded APCs, efficiently blocked both the trans and the cis infection of T cells. These findings highlight the major contributions of various mucosal cells in HIV dissemination and suggest that HIV hijacks the different properties of APCs to favor its dissemination through the body. They emphasize the role of macrophages in the rapid transmission of HIV to T lymphocytes at mucosal sites, dendritic cells being prone to migration to lymphoid organ for subsequent dissemination by cis transfer.

Langerhans cells in odontogenic epithelia of odontogenic fibromas

Langerhans cell (LC) is an antigen-presenting cell that is very important for T-cell-mediated immune reactions. Our previous studies have shown the presence of LCs in some odontogenic tumors and cysts. In this study, we further examined the presence of LCs in odontogenic epithelia of 16 odontogenic fibromas (OFs). Anti-CD1a and anti-S-100 immunostains were used to detect the presence of LCs in nests or strands of odontogenic epithelia of 16 OFs. These 16 OFs included 10 peripheral OFs excised from seven male and three female patients (mean age, 38 years) and six central OFs (including one recurrent OF) removed from five male patients (mean age, 28 years). Of the 10 peripheral OFs, six were found on the mandibular gingiva and four on the maxillary gingiva. Four central OFs were located in the maxilla and two in the mandible. We found that both anti-CD1a and anti-S-100 immunostains had an equal ability to identify LCs in OFs. Positively stained dendritic LCs could be detected in nests and strands of odontogenic epithelia in nine (six peripheral and three central OFs) of the 16 OFs. In five peripheral OFs, dendritic LCs were found in occasional nests or strands of odontogenic epithelia. In one peripheral and three central OFs, dendritic LCs could be detected in at least half of the nests or strands of odontogenic epithelium in the tissue section. LCs can be detected in the nests or strands of odontogenic epithelia in approximately 60% of the 10 peripheral OFs and approximately 50% of the six central OFs detected.

VEGF and p53 Biomarkers in Pediatric Patients With Langerhans Cell Histiocytosis

Langerhans cell histiocytosis (LCH) is a rare disease with abnormal accumulation of the dendritic Langerhans cells. In the localized form (single system), the disease is self-limiting but in the cases of multisystem disease, one third of the patients develop organ dysfunction with poor prognosis. The aim of this study was to examine the role of p53 and vascular endothelial growth factor (VEGF) in the pathogenesis of LCH and look for association of them with the extent of the disease. Biopsy specimens obtained from 26 patients with definitive diagnosis of LCH were stained immunohistochemically for p53 and VEGF. There were 13 male and 13 female cases. The mean age of patients at presentation was 41.9 months (range, 2 mo to 18 y). Multisystem disease was presented by 61% of the patients (8 boys and 8 girls). Patients with multisystem disease were on average older than those with single system disease. p53 protein could be detected in 92% of cases and 61.5% of patients expressed VEGF, mostly from multisystem group. These findings highlight the role of angiogenic factors in the clinical behavior of LCH and might be of prognostic or therapeutic importance. However, further studies, with larger sample sizes are warranted.

Sarcoptes scabiei mites modulate gene expression in human skin equivalents.

The ectoparasitic mite, Sarcoptes scabiei that burrows in the epidermis of mammalian skin has a long co-evolution with its hosts. Phenotypic studies show that the mites have the ability to modulate cytokine secretion and expression of cell adhesion molecules in cells of the skin and other cells of the innate and adaptive immune systems that may assist the mites to survive in the skin. The purpose of this study was to identify genes in keratinocytes and fibroblasts in human skin equivalents (HSEs) that changed expression in response to the burrowing of live scabies mites. Overall, of the more than 25,800 genes measured, 189 genes were up-regulated >2-fold in response to scabies mite burrowing while 152 genes were down-regulated to the same degree. HSEs differentially expressed large numbers of genes that were related to host protective responses including those involved in immune response, defense response, cytokine activity, taxis, response to other organisms, and cell adhesion. Genes for the expression of interleukin-1α (IL-1α) precursor, IL-1β, granulocyte/macrophage-colony stimulating factor (GM-CSF) precursor, and G-CSF precursor were up-regulated 2.8- to 7.4-fold, paralleling cytokine secretion profiles. A large number of genes involved in epithelium development and keratinization were also differentially expressed in response to live scabies mites. Thus, these skin cells are directly responding as expected in an inflammatory response to products of the mites and the disruption of the skin’s protective barrier caused by burrowing. This suggests that in vivo the interplay among these skin cells and other cell types, including Langerhans cells, dendritic cells, lymphocytes and endothelial cells, is responsible for depressing the host’s protective response allowing these mites to survive in the skin.

P1.007 Immune-Response in Lesional Skin of Secondary Syphilis

BackgroundIt is well known that tissue immune response plays an important role in the pathogenetic mechanisms of several bacterial and viral infections. Several studies focused on the cutaneous host immune-response...

Langerhans Cells in the Human Tympanic Membrane in Health and Disease

The normal tympanic membrane contains Langerhans dendritic cells, and they play a role in the pathogenesis of chronic suppurative otitis media. The presence of Langerhans dendritic cells in the normal tympanic membrane is disputed. However, they have been identified in tympanic membranes of patients with otitis media. A quantitative analysis of the distribution and morphology of these cells in the types of chronic suppurative otitis media has not been undertaken. Samples of normal cadaveric tympanic membranes and those from patients with chronic suppurative otitis media of the tubotympanic and atticoantral varieties were stained with the immunohistochemical marker CD1a. The number of cells per unit length of basement membrane, diameters of cells, and number and length of dendritic processes were compared between the groups. CD1a-positive Langerhans dendritic cells were present in the normal tympanic membrane. The number of cells per unit length of basement membrane, diameters of cells, and the length of dendritic processes increased significantly in tubotympanic disease and in atticoantral disease, the difference being more pronounced in the latter form of otitis media. Langerhans cells are present in the normal tympanic membrane, and they probably play differing roles in the pathogenesis of tubotympanic and atticoantral forms of chronic suppurative otitis media.